The final English and French versions of the Health Canada adopted ICH
guidance: Good Clinical Practice were revised due to Post Step 4 editorial
corrections agreed to by the Steering Committee on 10 June 1996. In addition,
the final French version was also revised due to translation errors. The
revised documents are now available and replace the previous versions.

Should you have any questions regarding the content of the guidance,
please contact

Guidance For Industry

Good Clinical Practice: Consolidated GuidelineICH Topic E6

Catalogue No. H42-2/67-11-1997EISBN 0-662-25953-X

Foreword

This guidance has been developed by the appropriate ICH Expert Working
Group and has been subject to consultation by the regulatory parties,
in accordance with the ICH Process. The ICH Steering Committee has endorsed
the final draft and recommended its adoption by the regulatory bodies
of the European Union, Japan and USA.

In adopting this ICH guidance, Health Canada endorses the principles
and practices described therein. This document should be read in conjunction
with the accompanying notice and the relevant sections of other applicable
guidances.

Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the policies
and governing statutes and regulations. They also serve to provide review
and compliance guidance to staff, thereby ensuring that mandates are implemented
in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach. Alternate approaches
to the principles and practices described in this document may
be acceptable provided they are supported by adequate scientific
justification. Alternate approaches should be discussed in advance with
the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health
Canada reserves the right to request information or material, or define
conditions not specifically described in this guidance, in order to allow
the Department to adequately assess the safety, efficacy or quality of
a therapeutic product. Health Canada is committed to ensuring that such
requests are justifiable and that decisions are clearly documented.

introduction

Good Clinical Practice (GCP) is an international ethical and scientific
quality standard for designing, conducting, recording and reporting trials
that involve the participation of human subjects. Compliance with this
standard provides public assurance that the rights, safety and well-being
of trial subjects are protected, consistent with the principles that have
their origin in the Declaration of Helsinki, and that the clinical trial
data are credible.

The objective of this ICHGCP guidance document is to provide a unified
standard for the European Union (EU), Japan and the United States to facilitate
the mutual acceptance of clinical data by the regulatory authorities in
these jurisdictions.

The guidance document was developed with consideration of the current
good clinical practices of the European Union, Japan, and the United States,
as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).

This guidance document should be followed when generating clinical trial
data that are intended to be submitted to regulatory authorities.

The principles established in this guidance document may also be applied
to other clinical investigations that may have an impact on the safety
and well-being of human subjects.

1. Glossary

1.1 Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal product
or its new usages, particularly as the therapeutic dose(s) may not be
established: all noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions. The phrase
responses to a medicinal product means that a causal relationship between
a medicinal product and an adverse event is at least a reasonable possibility,
i.e., the relationship cannot be ruled out.

Regarding marketed medicinal products: a response to a drug which is
noxious and unintended and which occurs at doses normally used in man
for prophylaxis, diagnosis, or therapy of diseases or for modification
of physiological function (see the ICH Guidance for Clinical Safety
Data Management: Definitions and Standards for Expedited Reporting).

1.2 Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation
subject administered a pharmaceutical product and which does not necessarily
have a causal relationship with this treatment. An adverse event (AE)
can therefore be any unfavourable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the
use of a medicinal (investigational) product, whether or not related to
the medicinal (investigational) product (see the ICH Guidance for Clinical
Safety Data Management: Definitions and Standards for Expedited Reporting).

1.3 Amendment (to the protocol)

See Protocol Amendment.

1.4 Applicable Regulatory Requirement(s)

Any law(s) and regulation(s) addressing the conduct of clinical trials
of investigational products.

1.5 Approval (in relation to Institutional Review Boards)

The affirmative decision of the IRB that the clinical trial has been
reviewed and may be conducted at the institution site within the constraints
set forth by the IRB, the institution, Good Clinical Practice (GCP), and
the applicable regulatory requirements.

1.6 Audit

A systematic and independent examination of trial related activities
and documents to determine whether the evaluated trial related activities
were conducted, and the data were recorded, analyzed and accurately reported
according to the protocol, sponsor's standard operating procedures (SOPs),
Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

1.7 Audit Certificate

A declaration of confirmation by the auditor that an audit has taken
place.

1.8 Audit Report

A written evaluation by the sponsor's auditor of the results of the audit.

1.9 Audit Trail

Documentation that allows reconstruction of the course of events.

1.10 Blinding/Masking

A procedure in which one or more parties to the trial are kept unaware
of the treatment assignment(s). Single-blinding usually refers to the
subject(s) being unaware, and double-blinding usually refers to the subject(s),
investigator(s), monitor, and, in some cases, data analyst(s) being unaware
of the treatment assignment(s).

1.11 Case Report Form (CRF)

A printed, optical, or electronic document designed to record all of
the protocol required information to be reported to the sponsor on each
trial subject.

1.12 Clinical Trial/Study

Any investigation in human subjects intended to discover or verify the
clinical, pharmacological and/or other pharmacodynamic effects of an investigational
product(s), and/or to identify any adverse reactions to an investigational
product(s), and/or to study absorption, distribution, metabolism, and
excretion of an investigational product(s) with the object of ascertaining
its safety and/or efficacy. The terms clinical trial and clinical study
are synonymous.

1.13 Clinical Trial/Study Report

A written description of a trial/study of any therapeutic, prophylactic,
or diagnostic agent conducted in human subjects, in which the clinical
and statistical description, presentations, and analyses are fully integrated
into a single report (see the ICH Guidance for Structure and Content
of Clinical Study Reports).

1.14 Comparator (Product)

An investigational or marketed product (i.e., active control), or placebo,
used as a reference in a clinical trial.

1.15 Compliance (in relation to trials)

Adherence to all the trial-related requirements, Good Clinical Practice
(GCP) requirements, and the applicable regulatory requirements.

1.16 Confidentiality

Prevention of disclosure, to other than authorized individuals, of a
sponsor's proprietary information or of a subject's identity.

1.17 Contract

A written, dated, and signed agreement between two or more involved parties
that sets out any arrangements on delegation and distribution of tasks
and obligations and, if appropriate, on financial matters. The protocol
may serve as the basis of a contract.

1.18 Coordinating Committee

A committee that a sponsor may organize to coordinate the conduct of
a multicentre trial.

1.19 Coordinating Investigator

An investigator assigned the responsibility for the coordination of investigators
at different centres participating in a multicentre trial.

1.20 Contract Research Organization (CRO)

A person or an organization (commercial, academic, or other) contracted
by the sponsor to perform one or more of a sponsor's trial-related duties
and functions.

1.21 Direct Access

Permission to examine, analyze, verify, and reproduce any records and
reports that are important to evaluation of a clinical trial. Any party
(e.g., domestic and foreign regulatory authorities, sponsor's monitors
and auditors) with direct access should take all reasonable precautions
within the constraints of the applicable regulatory requirement(s) to
maintain the confidentiality of subjects' identities and sponsor's proprietary
information.

1.22 Documentation

All records, in any form (including, but not limited to, written, electronic,
magnetic, and optical records, and scans, x-rays, and electrocardiograms)
that describe or record the methods, conduct, and/or results of a trial,
the factors affecting a trial, and the actions taken.

1.23 Essential Documents

Documents which individually and collectively permit evaluation of the
conduct of a study and the quality of the data produced (see 8. Essential
Documents for the Conduct of a Clinical Trial).

1.24 Good Clinical Practice (GCP)

A standard for the design, conduct, performance, monitoring, auditing,
recording, analyses, and reporting of clinical trials that provides assurance
that the data and reported results are credible and accurate, and that
the rights, integrity, and confidentiality of trial subjects are protected.

An independent data-monitoring committee that may be established by the
sponsor to assess at intervals the progress of a clinical trial, the safety
data, and the critical efficacy endpoints, and to recommend to the sponsor
whether to continue, modify, or stop a trial.

1.26 Impartial Witness

A person, who is independent of the trial, who cannot be unfairly influenced
by people involved with the trial, who attends the informed consent process
if the subject or the subject's legally acceptable representative cannot
read, and who reads the informed consent form and any other written information
supplied to the subject.

1.27 Independent Ethics Committee (IEC)

An independent body (a review board or a committee, institutional, regional,
national, or supranational), constituted of medical professionals and
non-medical members, whose responsibility it is to ensure the protection
of the rights, safety and well-being of human subjects involved in a trial
and to provide public assurance of that protection, by, among other things,
reviewing and approving/providing favourable opinion on, the trial protocol,
the suitability of the investigator(s), facilities, and the methods and
material to be used in obtaining and documenting informed consent of the
trial subjects.

The legal status, composition, function, operations and regulatory requirements
pertaining to Independent Ethics Committees may differ among countries,
but should allow the Independent Ethics Committee to act in agreement
with GCP as described in this guidance document.

1.28 Informed Consent

A process by which a subject voluntarily confirms his or her willingness
to participate in a particular trial, after having been informed of all
aspects of the trial that are relevant to the subject's decision to participate.
Informed consent is documented by means of a written, signed and dated
informed consent form.

1.29 Inspection

The act by a regulatory authority(ies) of conducting an official review
of documents, facilities, records, and any other resources that are deemed
by the authority(ies) to be related to the clinical trial and that may
be located at the site of the trial, at the sponsor's and/or contract
research organization's (CRO's) facilities, or at other establishments
deemed appropriate by the regulatory authority(ies).

1.30 Institution (medical)

Any public or private entity or agency or medical or dental facility
where clinical trials are conducted.

1.31 Institutional Review Board (IRB)

An independent body constituted of medical, scientific, and non-scientific
members, whose responsibility is to ensure the protection of the rights,
safety and well-being of human subjects involved in a trial by, among
other things, reviewing, approving, and providing continuing review of
trial protocol and amendments and of the methods and material to be used
in obtaining and documenting informed consent of the trial subjects.

1.32 Interim Clinical Trial/Study Report

A report of intermediate results and their evaluation based on analyses
performed during the course of a trial.

1.33 Investigational Product

A pharmaceutical form of an active ingredient or placebo being tested
or used as a reference in a clinical trial, including a product with a
marketing authorization when used or assembled (formulated or packaged)
in a way different from the approved form, or when used for an unapproved
indication, or when used to gain further information about an approved
use.

1.34 Investigator

A person responsible for the conduct of the clinical trial at a trial
site. If a trial is conducted by a team of individuals at a trial site,
the investigator is the responsible leader of the team and may be called
the principal investigator. See also Subinvestigator.

1.35 Investigator / Institution

An expression meaning "the investigator and/or institution, where
required by the applicable regulatory requirements".

1.36 Investigator's Brochure

A compilation of the clinical and nonclinical data on the investigational
product(s) which is relevant to the study of the investigational product(s)
in human subjects (see 7. Investigator's Brochure)

1.37 Legally Acceptable Representative

An individual or juridical or other body authorized under applicable
law to consent, on behalf of a prospective subject, to the subject's participation
in the clinical trial.

1.38 Monitoring

The act of overseeing the progress of a clinical trial, and of ensuring
that it is conducted, recorded, and reported in accordance with the protocol,
Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and
the applicable regulatory requirement(s).

1.39 Monitoring Report

A written report from the monitor to the sponsor after each site visit
and/or other trial-related communication according to the sponsor's SOPs.

1.40 Multicentre Trial

A clinical trial conducted according to a single protocol but at more
than one site, and therefore, carried out by more than one investigator.

1.41 Nonclinical Study

Biomedical studies not performed on human subjects.

1.42 Opinion (in relation to Independent Ethics Committee)

The judgement and/or the advice provided by an Independent Ethics Committee
(IEC).

1.43 Original Medical Record

See Source Documents.

1.44 Protocol

A document that describes the objective(s), design, methodology, statistical
considerations, and organization of a trial. The protocol usually also
gives the background and rationale for the trial, but these could be provided
in other protocol referenced documents. Throughout the ICHGCP Guidance
the term protocol refers to protocol and protocol amendments.

1.45 Protocol Amendment

A written description of a change(s) to or formal clarification of a
protocol.

1.46 Quality Assurance (QA)

All those planned and systematic actions that are established to ensure
that the trial is performed and the data are generated, documented (recorded),
and reported in compliance with Good Clinical Practice (GCP) and the applicable
regulatory requirement(s).

1.47 Quality Control (QC)

The operational techniques and activities undertaken within the quality
assurance system to verify that the requirements for quality of the trial-related
activities have been fulfilled.

1.48 Randomization

The process of assigning trial subjects to treatment or control groups
using an element of chance to determine the assignments in order to reduce
bias.

1.49 Regulatory Authorities

Bodies having the power to regulate. In the ICHGCP guidance the expression
Regulatory Authorities includes the authorities that review submitted
clinical data and those that conduct inspections (see 1.29). These bodies
are sometimes referred to as competent authorities.

is a congenital anomaly/birth defect (see the ICH Guidance for Clinical Safety Data Management: Definitions
and Standards for Expedited Reporting).

1.51 Source Data

All information in original records and certified copies of original
records of clinical findings, observations, or other activities in a clinical
trial necessary for the reconstruction and evaluation of the trial. Source
data are contained in source documents (original records or certified
copies).

1.52 Source Documents

Original documents, data, and records (e.g., hospital records, clinical
and office charts, laboratory notes, memoranda, subjects' diaries or evaluation
checklists, pharmacy dispensing records, recorded data from automated
instruments, copies or transcriptions certified after verification as
being accurate copies, microfiches, photographic negatives, microfilm
or magnetic media, x-rays, subject files, and records kept at the pharmacy,
at the laboratories and at medico-technical departments involved in the
clinical trial).

1.53 Sponsor

An individual, company, institution, or organization which takes responsibility
for the initiation, management, and/or financing of a clinical trial.

1.54 Sponsor-Investigator

An individual who both initiates and conducts, alone or with others,
a clinical trial, and under whose immediate direction the investigational
product is administered to, dispensed to, or used by a subject. The term
does not include any person other than an individual (e.g., it does not
include a corporation or an agency). The obligations of a sponsor-investigator
include both those of a sponsor and those of an investigator.

1.55 Standard Operating Procedures (SOPs)

Detailed, written instructions to achieve uniformity of the performance
of a specific function.

1.56 Subinvestigator

Any individual member of the clinical trial team designated and supervised
by the investigator at a trial site to perform critical trial-related
procedures and/or to make important trial-related decisions (e.g., associates,
residents, research fellows). See also Investigator.

1.57 Subject/Trial Subject

An individual who participates in a clinical trial, either as a recipient
of the investigational product(s) or as a control.

1.58 Subject Identification Code

A unique identifier assigned by the investigator to each trial subject
to protect the subject's identity and used in lieu of the subject's name
when the investigator reports adverse events and/or other trial related
data.

1.59 Trial Site

The location(s) where trial-related activities are actually conducted.

1.60 Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent
with the applicable product information (e.g., Investigator's Brochure
for an unapproved investigational product or package insert/summary of
product characteristics for an approved product) (see the ICH Guidance
for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting).

1.61 Vulnerable Subjects

Individuals whose willingness to volunteer in a clinical trial may be
unduly influenced by the expectation, whether justified or not, of benefits
associated with participation, or of a retaliatory response from senior
members of a hierarchy in case of refusal to participate. Examples are
members of a group with a hierarchical structure, such as medical, pharmacy,
dental, and nursing students, subordinate hospital and laboratory personnel,
employees of the pharmaceutical industry, members of the armed forces,
and persons kept in detention. Other vulnerable subjects include patients
with incurable diseases, persons in nursing homes, unemployed or impoverished
persons, patients in emergency situations, ethnic minority groups, homeless
persons, nomads, refugees, minors, and those incapable of giving consent.

1.62 Well-being (of the trial subjects)

The physical and mental integrity of the subjects participating in a
clinical trial.

2. The Principles Of ICHGCP

2.1 Clinical trials should be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki, and
that are consistent with GCP and the applicable regulatory requirement(s).

2.2 Before a trial is initiated, foreseeable risks and inconveniences
should be weighed against the anticipated benefit for the individual trial
subject and society. A trial should be initiated and continued only if
the anticipated benefits justify the risks.

2.3 The rights, safety, and well-being of the trial subjects are the
most important considerations and should prevail over interests of science
and society.

2.4 The available nonclinical and clinical information on an investigational
product should be adequate to support the proposed clinical trial.

2.5 Clinical trials should be scientifically sound, and described in
a clear, detailed protocol.

2.6 A trial should be conducted in compliance with the protocol that
has received prior institutional review board (IRB)/independent ethics
committee (IEC) approval/favourable opinion.

2.7 The medical care given to, and medical decisions made on behalf of,
subjects should always be the responsibility of a qualified physician
or, when appropriate, of a qualified dentist.

2.8 Each individual involved in conducting a trial should be qualified
by education, training, and experience to perform his or her respective
task(s).

2.9 Freely given informed consent should be obtained from every subject
prior to clinical trial participation.

2.10 All clinical trial information should be recorded, handled, and
stored in a way that allows its accurate reporting, interpretation and
verification.

2.11 The confidentiality of records that could identify subjects should
be protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirement(s).

2.12 Investigational products should be manufactured, handled, and stored
in accordance with applicable good manufacturing practice (GMP). They
should be used in accordance with the approved protocol.

2.13 Systems with procedures that assure the quality of every aspect
of the trial should be implemented.

3. Institutional Review Board/independent Ethics Committee
(IRB/IEC)

3.1 Responsibilities

3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being
of all trial subjects. Special attention should be paid to trials that
may include vulnerable subjects.

3.1.2 The IRB/IEC should obtain the following documents: trial
protocol(s)/amendment(s), written informed consent form(s) and consent
form updates that the investigator proposes for use in the trial, subject
recruitment procedures (e.g., advertisements), written information to
be provided to subjects, Investigator's Brochure (IB), available safety
information, information about payments and compensation available to
subjects, the investigator's current curriculum vitae and/or other documentation
evidencing qualifications, and any other documents that the IRB/IEC may
need to fulfil its responsibilities.

The IRB/IEC should review a proposed clinical trial within a reasonable
time and document its views in writing, clearly identifying the trial,
the documents reviewed and the dates for the following:

approval/favourable opinion;

modifications required prior to its approval/favourable opinion;

disapproval/negative opinion; and

termination/suspension of any prior approval/favourable opinion.

3.1.3 The IRB/IEC should consider the qualifications of the investigator
for the proposed trial, as documented by a current curriculum vitae and/or
by any other relevant documentation the IRB/IEC requests.

3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial
at intervals appropriate to the degree of risk to human subjects, but
at least once per year.

3.1.5 The IRB/IEC may request more information than is outlined in paragraph
4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the
additional information would add meaningfully to the protection of the
rights, safety and/or well-being of the subjects.

3.1.6 When a non-therapeutic trial is to be carried out with the consent
of the subject's legally acceptable representative (see 4.8.12, 4.8.14),
the IRB/IEC should determine that the proposed protocol and/or other document(s)
adequately addresses relevant ethical concerns and meets applicable regulatory
requirements for such trials.

3.1.7 Where the protocol indicates that prior consent of the trial subject
or the subject's legally acceptable representative is not possible (see
4.8.15), the IRB/IEC should determine that the proposed protocol and/or
other document(s) adequately addresses relevant ethical concerns and meets
applicable regulatory requirements for such trials (i.e., in emergency
situations).

3.1.8 The IRB/IEC should review both the amount and method of payment
to subjects to assure that neither presents problems of coercion or undue
influence on the trial subjects. Payments to a subject should be prorated
and not wholly contingent on completion of the trial by the subject.

3.1.9 The IRB/IEC should ensure that information regarding payment to
subjects, including the methods, amounts, and schedule of payment to trial
subjects, is set forth in the written informed consent form and any other
written information to be provided to subjects. The way payment will be
prorated should be specified.

3.2 Composition, Functions and Operations

3.2.1 The IRB/IEC should consist of a reasonable number of members,
who collectively have the qualifications and experience to review and
evaluate the science, medical aspects, and ethics of the proposed trial.
It is recommended that the IRB/IEC should include:

At least five members.

At least one member whose primary area of interest is in a nonscientific area.

At least one member who is independent of the institution/trial site.

Only those IRB/IEC members who are independent of the investigator and
the sponsor of the trial should vote/provide opinion on a trial-related
matter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.2 The IRB/IEC should perform its functions according to written operating
procedures, should maintain written records of its activities and minutes
of its meetings, and should comply with GCP and with the applicable regulatory
requirement(s).

3.2.3 An IRB/IEC should make its decisions at announced meetings at
which at least a quorum, as stipulated in its written operating procedures,
is present.

3.2.4 Only members who participate in the IRB/IEC review and discussion
should vote/provide their opinion and/or advise.

3.2.5 The investigator may provide information on any aspect of the
trial, but should not participate in the deliberations of the IRB/IEC
or in the vote/opinion of the IRB/IEC.

3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas
for assistance.

3.3 Procedures

The IRB/IEC should establish, document in writing, and follow its procedures,
which should include:

3.3.1 Determining its composition (names and qualifications of the members)
and the authority under which it is established.

3.3.2 Scheduling, notifying its members of, and conducting its meetings.

3.3.3 Conducting initial and continuing review of trials.

3.3.4 Determining the frequency of continuing review, as appropriate.

3.3.5 Providing, according to the applicable regulatory requirements,
expedited review and approval/favourable opinion of minor change(s) in
ongoing trials that have the approval/favourable opinion of the IRB/IEC.

3.3.6 Specifying that no subject should be admitted to a trial before
the IRB/IEC issues its written approval/favourable opinion of the trial.

3.3.7 Specifying that no deviations from, or changes of, the protocol
should be initiated without prior written IRB/IEC approval/favourable
opinion of an appropriate amendment, except when necessary to eliminate
immediate hazards to the subjects or when the change(s) involves only
logistical or administrative aspects of the trial (e.g., change of monitor(s),
telephone number(s)) (see 4.5.2).

3.3.8 Specifying that the investigator should promptly report to the
IRB/IEC:

Changes increasing the risk to subjects and/or affecting significantly
the conduct of the trial (see 4.10.2).

All adverse drug reactions (ADRs) that are both serious and unexpected.

New information that may affect adversely the safety of the subjects or the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
concerning:

Its trial-related decisions/opinions.

The reasons for its decisions/opinions.

Procedures for appeal of its decisions/opinions.

3.4 Records

The IRB/IEC should retain all relevant records (e.g., written procedures,
membership lists, lists of occupations/affiliations of members, submitted
documents, minutes of meetings, and correspondence) for a period of at
least 3 years after completion of the trial and make them available upon
request from the regulatory authority(ies).

The IRB/IEC may be asked by investigators, sponsors or regulatory authorities
to provide its written procedures and membership lists.

4. Investigator

4.1 Investigator's Qualifications and Agreements

4.1.1 The investigator(s) should be qualified by education, training,
and experience to assume responsibility for the proper conduct of the
trial, should meet all the qualifications specified by the applicable
regulatory requirement(s), and should provide evidence of such qualifications
through up-to-date curriculum vitae and/or other relevant documentation
requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).

4.1.2 The investigator should be thoroughly familiar with the appropriate
use of the investigational product(s), as described in the protocol, in
the current Investigator's Brochure, in the product information and in
other information sources provided by the sponsor.

4.1.3 The investigator should be aware of, and should comply with, GCP
and the applicable regulatory requirements.

4.1.4 The investigator/institution should permit monitoring and auditing
by the sponsor, and inspection by the appropriate regulatory authority(ies).

4.1.5 The investigator should maintain a list of appropriately qualified
persons to whom the investigator has delegated significant trial-related
duties.

4.2 Adequate Resources

4.2.1 The investigator should be able to demonstrate (e.g., based on
retrospective data) a potential for recruiting the required number of
suitable subjects within the agreed recruitment period.

4.2.2 The investigator should have sufficient time to properly conduct
and complete the trial within the agreed trial period.

4.2.3 The investigator should have available an adequate number of qualified
staff and adequate facilities for the foreseen duration of the trial to
conduct the trial properly and safely.

4.2.4 The investigator should ensure that all persons assisting with
the trial are adequately informed about the protocol, the investigational
product(s), and their trial-related duties and functions.

4.3 Medical Care of Trial Subjects

4.3.1 A qualified physician (or dentist, when appropriate), who is an
investigator or a sub-investigator for the trial, should be responsible
for all trial-related medical (or dental) decisions.

4.3.2 During and following a subject's participation in a trial, the
investigator/institution should ensure that adequate medical care is provided
to a subject for any adverse events, including clinically significant
laboratory values, related to the trial. The investigator/institution
should inform a subject when medical care is needed for intercurrent illness(es)
of which the investigator becomes aware.

4.3.3 It is recommended that the investigator inform the subject's primary
physician about the subject's participation in the trial if the subject
has a primary physician and if the subject agrees to the primary physician
being informed.

4.3.4 Although a subject is not obliged to give his/her reason(s) for
withdrawing prematurely from a trial, the investigator should make a reasonable
effort to ascertain the reason(s), while fully respecting the subject's
rights.

4.4 Communication with IRB/IEC

4.4.1 Before initiating a trial, the investigator/institution should
have written and dated approval/favourable opinion from the IRB/IEC for
the trial protocol, written informed consent form, consent form updates,
subject recruitment procedures (e.g., advertisements), and any other written
information to be provided to subjects.

4.4.2 As part of the investigator's/institution's written application
to the IRB/IEC, the investigator/institution should provide the IRB/IEC
with a current copy of the Investigator's Brochure. If the Investigator's
Brochure is updated during the trial, the investigator/institution should
supply a copy of the updated Investigator's Brochure to the IRB/IEC.

4.4.3 During the trial the investigator/institution should provide to
the IRB/IEC all documents subject to review.

4.5 Compliance with Protocol

4.5.1 The investigator/institution should conduct the trial in compliance
with the protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies) and which was given approval/favourable opinion by the
IRB/IEC. The investigator/institution and the sponsor should sign the
protocol, or an alternative contract, to confirm agreement.

4.5.2 The investigator should not implement any deviation from, or changes
of the protocol without agreement by the sponsor and prior review and
documented approval/favourable opinion from the IRB/IEC of an amendment,
except where necessary to eliminate an immediate hazard(s) to trial subjects,
or when the change(s) involves only logistical or administrative aspects
of the trial (e.g., change in monitor(s), change of telephone number(s)).

4.5.3 The investigator, or person designated by the investigator, should
document and explain any deviation from the approved protocol.

4.5.4 The investigator may implement a deviation from, or a change of,
the protocol to eliminate an immediate hazard(s) to trial subjects without
prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented
deviation or change, the reasons for it, and, if appropriate, the proposed
protocol amendment(s) should be submitted:

to the IRB/IEC for review and approval/favourable opinion,

to the sponsor for agreement and, if required,

to the regulatory authority(ies).

4.6 Investigational Product(s)

4.6.1 Responsibility for investigational product(s) accountability at
the trial
site(s) rests with the investigator/institution.

4.6.2 Where allowed/required, the investigator/institution may/should
assign some or all of the investigator's/institution's duties for investigational
product(s) accountability at the trial site(s) to an appropriate pharmacist
or another appropriate individual who is under the supervision of the
investigator/institution.

4.6.3 The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should
maintain records of the product's delivery to the trial site, the inventory
at the site, the use by each subject, and the return to the sponsor or
alternative disposition of unused product(s). These records should include
dates, quantities, batch/serial numbers, expiration dates (if applicable),
and the unique code numbers assigned to the investigational product(s)
and trial subjects. Investigators should maintain records that document
adequately that the subjects were provided the doses specified by the
protocol and reconcile all investigational product(s) received from the
sponsor.

4.6.4 The investigational product(s) should be stored as specified by
the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable
regulatory requirement(s).

4.6.5 The investigator should ensure that the investigational product(s)
are used only in accordance with the approved protocol.

4.6.6 The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to each
subject and should check, at intervals appropriate for the trial, that
each subject is following the instructions properly.

4.7 Randomization Procedures and Unblinding

The investigator should follow the trial's randomization procedures,
if any, and should ensure that the code is broken only in accordance with
the protocol. If the trial is blinded, the investigator should promptly
document and explain to the sponsor any premature unblinding (e.g., accidental
unblinding, unblinding due to a serious adverse event) of the investigational
product(s).

4.8 Informed Consent of Trial Subjects

4.8.1 In obtaining and documenting informed consent, the investigator
should comply with the applicable regulatory requirement(s), and should
adhere to GCP and to the ethical principles that have their origin in
the Declaration of Helsinki. Prior to the beginning of the trial, the
investigator should have the IRB/IEC's written approval/favourable opinion
of the written informed consent form and any other written information
to be provided to subjects.

4.8.2 The written informed consent form and any other written information
to be provided to subjects should be revised whenever important new information
becomes available that may be relevant to the subject's consent. Any revised
written informed consent form, and written information should receive
the IRB/IEC's approval/favourable opinion in advance of use. The subject
or the subject's legally acceptable representative should be informed
in a timely manner if new information becomes available that may be relevant
to the subject's willingness to continue participation in the trial. The
communication of this information should be documented.

4.8.3 Neither the investigator, nor the trial staff, should coerce or
unduly influence a subject to participate or to continue to participate
in a trial.

4.8.4 None of the oral and written information concerning the trial,
including the written informed consent form, should contain any language
that causes the subject or the subject's legally acceptable representative
to waive or to appear to waive any legal rights, or that releases or appears
to release the investigator, the institution, the sponsor, or their agents
from liability for negligence.

4.8.5 The investigator, or a person designated by the investigator, should
fully inform the subject or, if the subject is unable to provide informed
consent, the subject's legally acceptable representative, of all pertinent
aspects of the trial including the written information and the approval/favourable
opinion by the IRB/IEC.

4.8.6 The language used in the oral and written information about the
trial, including the written informed consent form, should be as non-technical
as practical and should be understandable to the subject or the subject's
legally acceptable representative and the impartial witness, where applicable.

4.8.7 Before informed consent may be obtained, the investigator, or
a person designated by the investigator, should provide the subject or
the subject's legally acceptable representative ample time and opportunity
to inquire about details of the trial and to decide whether or not to
participate in the trial. All questions about the trial should be answered
to the satisfaction of the subject or the subject's legally acceptable
representative.

4.8.8 Prior to a subject's participation in the trial, the written informed
consent form should be signed and personally dated by the subject or by
the subject's legally acceptable representative, and by the person who
conducted the informed consent discussion.

4.8.9 If a subject is unable to read or if a legally acceptable representative
is unable to read, an impartial witness should be present during the entire
informed consent discussion. After the written informed consent form and
any other written information to be provided to subjects, is read and
explained to the subject or the subject's legally acceptable representative,
and after the subject or the subject's legally acceptable representative
has orally consented to the subject's participation in the trial and,
if capable of doing so, has signed and personally dated the informed consent
form, the witness should sign and personally date the consent form. By
signing the consent form, the witness attests that the information in
the consent form and any other written information was accurately explained
to, and apparently understood by, the subject or the subject's legally
acceptable representative, and that informed consent was freely given
by the subject or the subject's legally acceptable representative.

4.8.10 Both the informed consent discussion and the written informed
consent form and any other written information to be provided to subjects
should include explanations of the following:

That the trial involves research.

The purpose of the trial.

The trial treatment(s) and the probability for random assignment to each treatment.

The trial procedures to be followed, including all invasive procedures.

The subject's responsibilities.

Those aspects of the trial that are experimental.

The reasonably foreseeable risks or inconveniences to the subject
and, when applicable, to an embryo, fetus, or nursing infant.

The reasonably expected benefits. When there is no intended clinical
benefit to the subject, the subject should be made aware of this.

The alternative procedure(s) or course(s) of treatment that may be
available to the subject, and their important potential benefits and
risks.

The compensation and/or treatment available to the subject in the
event of trial-related injury.

The anticipated prorated payment, if any, to the subject for participating
in the trial.

The anticipated expenses, if any, to the subject for participating
in the trial.

That the subject's participation in the trial is voluntary and that
the subject may refuse to participate or withdraw from the trial, at
any time, without penalty or loss of benefits to which the subject is
otherwise entitled.

That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject's original
medical records for verification of clinical trial procedures and/or
data, without violating the confidentiality of the subject, to the extent
permitted by the applicable laws and regulations and that, by signing
a written informed consent form, the subject or the subject's legally
acceptable representative is authorizing such access.

That records identifying the subject will be kept confidential and,
to the extent permitted by the applicable laws and/or regulations, will
not be made publicly available. If the results of the trial are published,
the subject's identity will remain confidential.

That the subject or the subject's legally acceptable representative
will be informed in a timely manner if information becomes available
that may be relevant to the subject's willingness to continue participation
in the trial.

The person(s) to contact for further information regarding the trial
and the rights of trial subjects, and whom to contact in the event of
trial-related injury.

The foreseeable circumstances and/or reasons under which the subject's
participation in the trial may be terminated.

The expected duration of the subject's participation in the trial.

The approximate number of subjects involved in the trial.

4.8.11 Prior to participation in the trial, the subject or the subject's
legally acceptable representative should receive a copy of the signed
and dated written informed consent form and any other written information
provided to the subjects. During a subject's participation in the trial,
the subject or the subject's legally acceptable representative should
receive a copy of the signed and dated consent form updates and a copy
of any amendments to the written information provided to subjects.

4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes
subjects who can only be enrolled in the trial with the consent of the
subject's legally acceptable representative (e.g., minors, or patients
with severe dementia), the subject should be informed about the trial
to the extent compatible with the subject's understanding and, if capable,
the subject should sign and personally date the written informed consent.

4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e.,
a trial in which there is no anticipated direct clinical benefit to the
subject), should be conducted in subjects who personally give consent
and who sign and date the written informed consent form.

4.8.14 Non-therapeutic trials may be conducted in subjects with consent
of a legally acceptable representative provided the following conditions
are fulfilled:

The objectives of the trial can not be met by means of a trial in
subjects who can give informed consent personally.

The foreseeable risks to the subjects are low.

The negative impact on the subject's well-being is minimized and
low.

The trial is not prohibited by law.

The approval/favourable opinion of the IRB/IEC is expressly sought
on the inclusion of such subjects, and the written approval/favourable
opinion covers this aspect.

Such trials, unless an exception is justified, should be conducted in
patients having a disease or condition for which the investigational product
is intended. Subjects in these trials should be particularly closely monitored
and should be withdrawn if they appear to be unduly distressed.

4.8.15 In emergency situations, when prior consent of the subject is
not possible, the consent of the subject's legally acceptable representative,
if present, should be requested. When prior consent of the subject is
not possible, and the subject's legally acceptable representative is not
available, enrollment of the subject should require measures described
in the protocol and/or elsewhere, with documented approval/favourable
opinion by the IRB/IEC, to protect the rights, safety and well-being of
the subject and to ensure compliance with applicable regulatory requirements.
The subject or the subject's legally acceptable representative should
be informed about the trial as soon as possible and consent to continue
and other consent as appropriate (see 4.8.10) should be requested.

4.9 Records and Reports

4.9.1 The investigator should ensure the accuracy, completeness, legibility,
and timeliness of the data reported to the sponsor in the CRFs and in
all required reports.

4.9.2 Data reported on the CRF, that are derived from source documents,
should be consistent with the source documents or the discrepancies should
be explained.

4.9.3 Any change or correction to a CRF should be dated, initialed,
and explained (if necessary) and should not obscure the original entry
(i.e., an audit trail should be maintained); this applies to both written
and electronic changes or corrections (see 5.18.4 (n)). Sponsors should
provide guidance to investigators and/or the investigators' designated
representatives on making such corrections. Sponsors should have written
procedures to assure that changes or corrections in CRFs made by sponsor's
designated representatives are documented, are necessary, and are endorsed
by the investigator. The investigator should retain records of the changes
and corrections.

4.9.4 The investigator/institution should maintain the trial documents
as specified in Essential Documents for the Conduct of a Clinical Trial
(see 8.) and as required by the applicable regulatory requirement(s).
The investigator/institution should take measures to prevent accidental
or premature destruction of these documents.

4.9.5 Essential documents should be retained until at least 2 years
after the last approval of a marketing application in an ICH region and
until there are no pending or contemplated marketing applications in an
ICH region or at least 2 years have elapsed since the formal discontinuation
of clinical development of the investigational product. These documents
should be retained for a longer period however if required by the applicable
regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as
to when these documents no longer need to be retained (see 5.5.12).

4.9.6 The financial aspects of the trial should be documented in an
agreement between the sponsor and the investigator/institution.

4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority,
the investigator/institution should make available for direct access all
requested trial-related records.

4.10 Progress Reports

4.10.1 The investigator should submit written summaries of the trial
status to the IRB/IEC annually, or more frequently, if requested by the
IRB/IEC.

4.10.2 The investigator should promptly provide written reports to the
sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution
on any changes significantly affecting the conduct of the trial, and/or
increasing the risk to subjects.

4.11 Safety Reporting

4.11.1 All serious adverse events (SAEs) should be reported immediately
to the sponsor except for those SAEs that the protocol or other document
(e.g., Investigator's Brochure) identifies as not needing immediate reporting.
The immediate reports should be followed promptly by detailed, written
reports. The immediate and follow-up reports should identify subjects
by unique code numbers assigned to the trial subjects rather than by the
subjects' names, personal identification numbers, and/or addresses. The
investigator should also comply with the applicable regulatory requirement(s)
related to the reporting of unexpected serious adverse drug reactions
to the regulatory authority(ies) and the IRB/IEC.

4.11.2 Adverse events and/or laboratory abnormalities identified in
the protocol as critical to safety evaluations should be reported to the
sponsor according to the reporting requirements and within the time periods
specified by the sponsor in the protocol.

4.11.3 For reported deaths, the investigator should supply the sponsor
and the IRB/IEC with any additional requested information (e.g., autopsy
reports and terminal medical reports).

4.12 Premature Termination or Suspension of a Trial

If the trial is prematurely terminated or suspended for any reason,
the investigator/institution should promptly inform the trial subjects,
should assure appropriate therapy and follow-up for the subjects, and,
where required by the applicable regulatory requirement(s), should inform
the regulatory authority(ies). In addition:

4.12.1 If the investigator terminates or suspends a trial without prior
agreement of the sponsor, the investigator should inform the institution
where applicable, and the investigator/institution should promptly inform
the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC
a detailed written explanation of the termination or suspension.

4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the
investigator should promptly inform the institution where applicable and
the investigator/institution should promptly inform the IRB/IEC and provide
the IRB/IEC a detailed written explanation of the termination or suspension.

4.12.3 If the IRB/IEC terminates or suspends its approval/favourable
opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform
the institution where applicable and the investigator/institution should
promptly notify the sponsor and provide the sponsor with a detailed written
explanation of the termination or suspension.

4.13 Final Report(s) by Investigator

Upon completion of the trial, the investigator, where applicable, should
inform the institution; the investigator/institution should provide the
IRB/IEC with a summary of the trial's outcome, and the regulatory authority(ies)
with any reports required.

5. Sponsor

5.1 Quality Assurance and Quality Control

5.1.1 The sponsor is responsible for implementing and maintaining quality
assurance and quality control systems with written SOPs to ensure that
trials are conducted and data are generated, documented (recorded), and
reported in compliance with the protocol, GCP, and the applicable regulatory
requirement(s).

5.1.2 The sponsor is responsible for securing agreement from all involved
parties to ensure direct access (see 1.21) to all trial related sites,
source data/documents, and reports for the purpose of monitoring and auditing
by the sponsor, and inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling
to ensure that all data are reliable and have been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution
and any other parties involved with the clinical trial, should be in writing,
as part of the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)

5.2.1 A sponsor may transfer any or all of the sponsor's trial-related
duties and functions to a CRO, but the ultimate responsibility for the
quality and integrity of the trial data always resides with the sponsor.
The CRO should implement quality assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and
assumed by a CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred
to and assumed by a CRO are retained by the sponsor.

5.2.4 All references to a sponsor in this guidance document also apply
to a CRO to the extent that a CRO has assumed the trial related duties
and functions of a sponsor.

5.3 Medical Expertise

The sponsor should designate appropriately qualified medical personnel
who will be readily available to advise on trial related medical questions
or problems. If necessary, outside consultant(s) may be appointed for
this purpose.

5.4 Trial Design

5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians,
clinical pharmacologists, and physicians) as appropriate, throughout all
stages of the trial process, from designing the protocol and CRFs and
planning the analyses to analyzing and preparing interim and final clinical
trial reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s)
(see 6.), the ICH Guidance for Structure and Content of Clinical Study
Reports, and other appropriate ICH guidance on trial design, protocol
and conduct.

5.5 Trial Management, Data Handling, and Record Keeping

5.5.1 The sponsor should utilize appropriately qualified individuals
to supervise the overall conduct of the trial, to handle the data, to
verify the data, to conduct the statistical analyses, and to prepare the
trial reports.

5.5.2 The sponsor may consider establishing an independent data-monitoring
committee (IDMC) to assess the progress of a clinical trial, including
the safety data and the critical efficacy endpoints at intervals, and
to recommend to the sponsor whether to continue, modify, or stop a trial.
The IDMC should have written operating procedures and maintain written
records of all its meetings.

Ensure and document that the electronic data processing system(s)
conforms to the sponsor's established requirements for completeness,
accuracy, reliability, and consistent intended performance (i.e., validation).

Maintains SOPs for using these systems.

Ensure that the systems are designed to permit data changes in such
a way that the data changes are documented and that there is no deletion
of entered data (i.e., maintain an audit trail, data trail, edit trail).

Maintain a security system that prevents unauthorized access to the
data.

Maintain a list of the individuals who are authorized to make data
changes (see 4.1.5 and 4.9.3).

Maintain adequate backup of the data.

Safeguard the blinding, if any (e.g., maintain the blinding during
data entry and processing).

5.5.4 If data are transformed during processing, it should always be
possible to compare the original data and observations with the processed
data.

5.5.5 The sponsor should use an unambiguous subject identification code
(see 1.58) that allows identification of all the data reported for each
subject.

5.5.6 The sponsor, or other owners of the data, should retain all of
the sponsor-specific essential documents pertaining to the trial (see
8. Essential Documents for the Conduct of a Clinical Trial).

5.5.7 The sponsor should retain all sponsor-specific essential documents
in conformance with the applicable regulatory requirement(s) of the country(ies)
where the product is approved, and/or where the sponsor intends to apply
for approval(s).

5.5.8 If the sponsor discontinues the clinical development of an investigational
product (i.e., for any or all indications, routes of administration, or
dosage forms), the sponsor should maintain all sponsor-specific essential
documents for at least 2 years after formal discontinuation or in conformance
with the applicable regulatory requirement(s).

5.5.9 If the sponsor discontinues the clinical development of an investigational
product, the sponsor should notify all the trial investigators/institutions
and all the regulatory authorities.

5.5.10 Any transfer of ownership of the data should be reported to the
appropriate authority(ies), as required by the applicable regulatory
requirement(s).

5.5.11 The sponsor-specific essential documents should be retained until
at least 2 years after the last approval of a marketing application in
an ICH region and until there are no pending or contemplated marketing
applications in an ICH region or at least 2 years have elapsed since the
formal discontinuation of clinical development of the investigational
product. These documents should be retained for a longer period however
if required by the applicable regulatory requirement(s) or if needed by
the sponsor.

5.5.12 The sponsor should inform the investigator(s)/institution(s)
in writing of the need for record retention and should notify the investigator(s)/institution(s)
in writing when the trial related records are no longer needed.

5.6 Investigator Selection

5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s).
Each investigator should be qualified by training and experience and should
have adequate resources (see 4.1, 4.2) to properly conduct the trial for
which the investigator is selected. If organization of a coordinating
committee and/or selection of coordinating investigator(s) are to be utilized
in multicentre trials, their organization and/or selection are the sponsor's
responsibility.

5.6.2 Before entering an agreement with an investigator/institution
to conduct a trial, the sponsor should provide the investigator(s)/institution(s)
with the protocol and an up-to-date Investigator's Brochure, and should
provide sufficient time for the investigator/institution to review the
protocol and the information provided.

5.6.3 The sponsor should obtain the investigator's/institution's agreement:

to conduct the trial in compliance with GCP, with the applicable
regulatory requirement(s) (see 4.1.3), and with the protocol agreed
to by the sponsor and given approval/favourable opinion by the IRB/IEC
(see 4.5.1);

to comply with procedures for data recording/reporting;

to permit monitoring, auditing and inspection (see 4.1.4) and

to retain the trial related essential documents until the sponsor
informs the investigator/institution these documents are no longer needed
(see 4.9.4 and 5.5.12).

The sponsor and the investigator/institution should sign the protocol,
or an alternative document, to confirm this agreement.

5.7 Allocation of Responsibilities

Prior to initiating a trial, the sponsor should define, establish, and
allocate all trial-related responsibilities.

5.8 Compensation to Subjects and Investigators

5.8.1 If required by the applicable regulatory requirement(s), the sponsor
should provide insurance or should indemnify (legal and financial coverage)
the investigator/the institution against claims arising from the trial,
except for claims that arise from malpractice and/or negligence.

5.8.2 The sponsor's policies and procedures should address the costs
of treatment of trial subjects in the event of trial-related injuries
in accordance with the applicable regulatory requirement(s).

5.8.3 When trial subjects receive compensation, the method and manner
of compensation should comply with applicable regulatory requirement(s).

5.9 Financing

The financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.

5.10 Notification/Submission to Regulatory Authority(ies)

Before initiating the clinical trial(s), the sponsor (or the sponsor
and the investigator, if required by the applicable regulatory requirement(s))
should submit any required application(s) to the appropriate authority(ies)
for review, acceptance, and/or permission (as required by the applicable
regulatory requirement(s))to begin the trial(s). Any notification/submission
should be dated and contain sufficient information to identify the protocol.

5.11 Confirmation of Review by IRB/IEC

5.11.1 The sponsor should obtain from the investigator/institution:

The name and address of the investigator's/institution's IRB/IEC.

A statement obtained from the IRB/IEC that it is organized and operates
according to GCP and the applicable laws and regulations.

Documented IRB/IEC approval/favourable opinion and, if requested
by the sponsor, a current copy of protocol, written informed consent
form(s) and any other written information to be provided to subjects,
subject recruiting procedures, and documents related to payments and
compensation available to the subjects, and any other documents that
the IRB/IEC may have requested.

5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon
change(s) in any aspect of the trial, such as modification(s) of the protocol,
written informed consent form and any other written information to be
provided to subjects, and/or other procedures, the sponsor should obtain
from the investigator/institution a copy of the modification(s) made and
the date approval/favourable opinion was given by the IRB/IEC.

5.11.3 The sponsor should obtain from the investigator/institution documentation
and dates of any IRB/IEC re-approvals/re-evaluations with favourable opinion,
and of any withdrawals or suspensions of approval/favourable opinion.

5.12 Information on Investigational Product(s)

5.12.1 When planning trials, the sponsor should ensure that sufficient
safety and efficacy data from nonclinical studies and/or clinical trials
are available to support human exposure by the route, at the dosages,
for the duration, and in the trial population to be studied.

5.12.2 The sponsor should update the Investigator's Brochure as significant
new information becomes available (see 7. Investigator's Brochure).

5.13.1 The sponsor should ensure that the investigational product(s)
(including active comparator(s) and placebo, if applicable) is characterized
as appropriate to the stage of development of the product(s), is manufactured
in accordance with any applicable GMP, and is coded and labelled in a
manner that protects the blinding, if applicable. In addition, the labelling
should comply with applicable regulatory requirement(s).

5.13.3 The investigational product(s) should be packaged to prevent
contamination and unacceptable deterioration during transport and storage.

5.13.4 In blinded trials, the coding system for the investigational
product(s) should include a mechanism that permits rapid identification
of the product(s) in case of a medical emergency, but does not permit
undetectable breaks of the blinding.

5.13.5 If significant formulation changes are made in the investigational
or comparator product(s) during the course of clinical development, the
results of any additional studies of the formulated product(s) (e.g.,
stability, dissolution rate, bioavailability) needed to assess whether
these changes would significantly alter the pharmacokinetic profile of
the product should be available prior to the use of the new formulation
in clinical trials.

5.14 Supplying and Handling Investigational Product(s)

5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s)
with the investigational product(s).

5.14.2 The sponsor should not supply an investigator/institution with
the investigational product(s) until the sponsor obtains all required
documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory
authority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructions
that the investigator/institution should follow for the handling and storage
of investigational product(s) for the trial and documentation thereof.
The procedures should address adequate and safe receipt, handling, storage,
dispensing, retrieval of unused product from subjects, and return of unused
investigational product(s) to the sponsor (or alternative disposition
if authorized by the sponsor and in compliance with the applicable regulatory
requirement(s)).

5.14.4 The sponsor should:

Ensure timely delivery of investigational product(s) to the investigator(s).

Maintain records that document shipment, receipt, disposition, return,
and destruction of the investigational product(s) (see 8. Essential
Documents for the Conduct of a Clinical Trial).

Maintain a system for retrieving investigational products and documenting
this retrieval (e.g., for deficient product recall, reclaim after trial
completion, expired product reclaim).

Maintain a system for the position of unused investigational product(s)
and for the documentation of this disposition.

5.14.5 The sponsor should:

Take steps to ensure that the investigational product(s) are stable
over the period of use.

Maintain sufficient quantities of the investigational product(s)
used in the trials to reconfirm specifications, should this become necessary,
and maintain records of batch sample analyses and characteristics. To
the extent stability permits, samples should be retained either until
the
analyses of the trial data are complete or as required by the applicable
regulatory requirement(s), whichever represents the longer retention
period.

5.15 Record Access

5.15.1 The sponsor should ensure that it is specified in the protocol
or other written agreement that the investigator(s)/institution(s) provide
direct access to source data/documents for trial-related monitoring, audits,
IRB/IEC review, and regulatory inspection.

5.15.2 The sponsor should verify that each subject has consented, in
writing, to direct access to his/her original medical records for trial-related
monitoring, audit, IRB/IEC review, and regulatory inspection.

5.16 Safety Information

5.16.1 The sponsor is responsible for the ongoing safety evaluation
of the investigational product(s).

5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s)
and the regulatory authority(ies) of findings that could affect adversely
the safety of subjects, impact the conduct of the trial, or alter the
IRB/IEC's approval/favourable opinion to continue the trial.

5.17 Adverse Drug Reaction Reporting

5.17.1 The sponsor should expedite the reporting to all concerned
investigator(s)/institution(s),
to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies)
of all adverse drug reactions (ADRs) that are both serious and unexpected.

5.17.2 Such expedited reports should comply with the applicable regulatory
requirement(s) and with the ICH Guidance for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting.

5.17.3 The sponsor should submit to the regulatory authority(ies) all
safety updates and periodic reports, as required by applicable regulatory
requirement(s).

5.18 Monitoring

5.18.1 Purpose

The purposes of trial monitoring are to verify that:

The rights and well-being of human subjects are protected.

The reported trial data are accurate, complete, and verifiable from
source documents.

The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory
requirement(s).

5.18.2 Selection and Qualifications of Monitors

Monitors should be appointed by the sponsor.

Monitors should be appropriately trained, and should have the scientific
and/or clinical knowledge needed to monitor the trial adequately. A
monitor's qualifications should be documented.

Monitors should be thoroughly familiar with the investigational product(s),
the protocol, written informed consent form and any other written information
to be provided to subjects, the sponsor's SOPs, GCP, and the applicable
regulatory requirement(s).

5.18.3 Extent and Nature of Monitoring

The sponsor should ensure that the trials are adequately monitored.
The sponsor should determine the appropriate extent and nature of monitoring.
The determination of the extent and nature of monitoring should be based
on considerations such as the objective, purpose, design, complexity,
blinding, size, and endpoints of the trial. In general there is a need
for on-site monitoring, before, during, and after the trial; however in
exceptional circumstances the sponsor may determine that central monitoring
in conjunction with procedures such as investigators' training and meetings,
and extensive written guidance can assure appropriate conduct of the trial
in accordance with GCP. Statistically controlled sampling may be an acceptable
method for selecting the data to be verified.

5.18.4 Monitor's Responsibilities

The monitor(s) in accordance with the sponsor's requirements should
ensure that the trial is conducted and documented properly by carrying
out the following activities when relevant and necessary to the trial
and the trial site:

Acting as the main line of communication between the sponsor and
the investigator.

Verifying that the investigator has adequate qualifications and resources
(see 4.1, 4.2, 5.6) and remain adequate throughout the trial period,
that facilities, including laboratories, equipment, and staff, are adequate
to safely and properly conduct the trial and remain adequate throughout
the trial period.

Verifying, for the investigational product(s):

That storage times and conditions are acceptable, and that supplies
are sufficient throughout the trial.

That the investigational product(s) are supplied only to subjects
who are eligible to receive it and at the protocol specified
dose(s).

That subjects are provided with necessary instruction on properly
using, handling, storing, and returning the investigational product(s).

That the receipt, use, and return of the investigational product(s)
at the trial sites are controlled and documented adequately.

That the disposition of unused investigational product(s) at
the trial sites complies with applicable regulatory requirement(s)
and is in accordance with the sponsor.

Verifying that the investigator follows the approved protocol and
all approved amendment(s), if any.

Verifying that written informed consent was obtained before each
subject's participation in the trial.

Ensuring that the investigator receives the current Investigator's
Brochure, all documents, and all trial supplies needed to conduct the
trial properly and to comply with the applicable regulatory
requirement(s).

Ensuring that the investigator and the investigator's trial staff
are adequately informed about the trial.

Verifying that the investigator and the investigator's trial staff
are performing the specified trial functions, in accordance with the
protocol and any other written agreement between the sponsor and the
investigator/institution, and have not delegated these functions to
unauthorized individuals.

Verifying that the investigator is enrolling only eligible subjects.

Reporting the subject recruitment rate.

Verifying that source documents and other trial records are accurate,
complete, kept up-to-date and maintained.

Verifying that the investigator provides all the required reports,
notifications, applications, and submissions, and that these documents
are accurate, complete, timely, legible, dated, and identify the trial.

Checking the accuracy and completeness of the CRF entries, source
documents and other trial-related records against each other. The monitor
specifically should verify that:

The data required by the protocol are reported accurately on
the CRFs and are consistent with the source documents.

Any dose and/or therapy modifications are well documented for
each of the trial subjects.

Adverse events, concomitant medications and intercurrent illnesses
are reported in accordance with the protocol on the CRFs.

Visits that the subjects fail to make, tests that are not conducted,
and examinations that are not performed are clearly reported as
such on the CRFs.

All withdrawals and dropouts of enrolled subjects from the trial
are reported and explained on the CRFs.

Informing the investigator of any CRF entry error, omission, or illegibility.
The monitor should ensure that appropriate corrections, additions, or
deletions are made, dated, explained (if necessary), and initialled
by the investigator or by a member of the investigator's trial staff
who is authorized to initial CRF changes for the investigator. This
authorization should be documented.

Determining whether all adverse events (AEs) are appropriately reported
within the time periods required by GCP, the protocol, the IRB/IEC,
the sponsor, and the applicable regulatory requirement(s).

Determining whether the investigator is maintaining the essential
documents (see 8. Essential Documents for the Conduct of a Clinical
Trial).

Communicating deviations from the protocol, SOPs, GCP, and the applicable
regulatory requirements to the investigator and taking appropriate action
designed to prevent recurrence of the detected deviations.

5.18.5 Monitoring Procedures

The monitor(s) should follow the sponsor's established written SOPs as
well as those procedures that are specified by the sponsor for monitoring
a specific trial.

5.18.6 Monitoring Report

The monitor should submit a written report to the sponsor after each
trial-site visit or trial-related communication.

Reports should include the date, site, name of the monitor, and name
of the investigator or other individual(s) contacted.

Reports should include a summary of what the monitor reviewed and
the monitor's statements concerning the significant findings/facts,
deviations and deficiencies, conclusions, actions taken or to be taken
and/or actions recommended to secure compliance.

The review and follow-up of the monitoring report with the sponsor
should be documented by the sponsor's designated representative.

5.19 Audit

If or when sponsors perform audits, as part of implementing quality assurance,
they should consider:

5.19.1 Purpose

The purpose of a sponsor's audit, which is independent of and separate
from routine monitoring or quality control functions, should be to evaluate
trial conduct and compliance with the protocol, SOPs, GCP, and the applicable
regulatory requirements.

5.19.2 Selection and Qualification of Auditors

The sponsor should appoint individuals, who are independent of the
clinical trials/systems, to conduct audits.

The sponsor should ensure that the auditors are qualified by training
and experience to conduct audits properly. An auditor's qualifications
should be documented.

5.19.3 Auditing Procedures

The sponsor should ensure that the auditing of clinical trials/systems
is conducted in accordance with the sponsor's written procedures on
what to audit, how to audit, the frequency of audits, and the form and
content of audit reports.

The sponsor's audit plan and procedures for a trial audit should
be guided by the importance of the trial to submissions to regulatory
authorities, the number of subjects in the trial, the type and complexity
of the trial, the level of risks to the trial subjects, and any identified
problem(s).

The observations and findings of the auditor(s) should be documented.

To preserve the independence and value of the audit function, the
regulatory authority(ies) should not routinely request the audit reports.
Regulatory authority(ies) may seek access to an audit report on a case
by case basis when evidence of serious GCP non-compliance exists, or
in the course of legal proceedings.

When required by applicable law or regulation, the sponsor should
provide an audit certificate.

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable
regulatory requirement(s) by an investigator/institution, or by member(s)
of the sponsor's staff should lead to prompt action by the sponsor to
secure compliance.

5.20.2 If the monitoring and/or auditing identifies serious and/or persistent
noncompliance on the part of an investigator/institution, the sponsor
should terminate the investigator's/institution's participation in the
trial. When an investigator's/institution's participation is terminated
because of noncompliance, the sponsor should notify promptly the regulatory
authority(ies).

5.21 Premature Termination or Suspension of a Trial

If a trial is prematurely terminated or suspended, the sponsor should
promptly inform the investigators/institutions, and the regulatory authority(ies)
of the termination or suspension and the reason(s) for the termination
or suspension. The IRB/IEC should also be informed promptly and provided
the reason(s) for the termination or suspension by the sponsor or by the
investigator/institution, as specified by the applicable regulatory requirement(s).

5.22 Clinical Trial/Study Reports

Whether the trial is completed or prematurely terminated, the sponsor
should ensure that the clinical trial reports are prepared and provided
to the regulatory agency(ies) as required by the applicable regulatory
requirement(s). The sponsor should also ensure that the clinical trial
reports in marketing applications meet the standards of the ICH Guidance
for Structure and Content of Clinical Study Reports. (NOTE: The
ICH Guidance for Structure and Content of Clinical Study Reports
specifies that abbreviated study reports may be acceptable in certain
cases.)

5.23 Multicentre Trials

For multicentre trials, the sponsor should ensure that:

5.23.1 All investigators conduct the trial in strict compliance with
the protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies), and given approval/favourable opinion by the IRB/IEC.

5.23.2 The CRFs are designed to capture the required data at all multicentre
trial sites. For those investigators who are collecting additional data,
supplemental CRFs should also be provided that are designed to capture
the additional data.

5.23.3 The responsibilities of coordinating investigator(s) and the
other participating investigators are documented prior to the start of
the trial.

5.23.4 All investigators are given instructions on following the protocol,
on complying with a uniform set of standards for the assessment of clinical
and laboratory findings, and on completing the CRFs.

6. Clinical Trial Protocol And Protocol Amendment(s)

The contents of a trial protocol should generally include the following
topics. However, site specific information may be provided on separate
protocol page(s), or addressed in a separate agreement, and some of the
information listed below may be contained in other protocol referenced
documents, such as an Investigator's Brochure.

6.1 General Information

6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s)
should also bear the amendment number(s) and date(s).

6.1.2 Name and address of the sponsor and monitor (if other than the
sponsor).

6.1.3 Name and title of the person(s) authorized to sign the protocol
and the protocol amendment(s) for the sponsor.

6.1.4 Name, title, address, and telephone number(s) of the sponsor's
medical expert (or dentist when appropriate) for the trial.

6.1.5 Name and title of the investigator(s) who is (are) responsible
for conducting the trial, and the address and telephone number(s) of the
trial
site(s).

6.1.6 Name, title, address, and telephone number(s) of the qualified
physician (or dentist, if applicable), who is responsible for all trial-site
related medical (or dental) decisions (if other than investigator).

6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other
medical and/or technical department(s) and/or institutions involved in
the trial.

6.2 Background Information

6.2.1 Name and description of the investigational product(s).

6.2.2 A summary of findings from nonclinical studies that potentially
have clinical significance and from clinical trials that are relevant
to the trial.

6.2.3 Summary of the known and potential risks and benefits, if any,
to human subjects.

6.2.4 Description of and justification for the route of administration,
dosage, dosage regimen, and treatment period(s).

6.2.5 A statement that the trial will be conducted in compliance with
the protocol, GCP and the applicable regulatory requirement(s).

6.2.6 Description of the population to be studied.

6.2.7 References to literature and data that are relevant to the trial,
and that provide background for the trial.

6.3 Trial Objectives and Purpose

A detailed description of the objectives and the purpose of the trial.

6.4 Trial Design

The scientific integrity of the trial and the credibility of the data
from the trial depend substantially on the trial design. A description
of the trial design, should include:

6.4.1 A specific statement of the primary endpoints and the secondary
endpoints, if any, to be measured during the trial.

6.4.2 A description of the type/design of trial to be conducted (e.g.,
double-blind, placebo-controlled, parallel design) and a schematic diagram
of trial design, procedures and stages.

6.4.3 A description of the measures taken to minimize/avoid bias, including:

Randomization.

Blinding.

6.4.4 A description of the trial treatment(s) and the dosage and dosage
regimen of the investigational product(s). Also include a description
of the dosage form, packaging, and labelling of the investigational product(s).

6.4.5 The expected duration of subject participation, and a description
of the sequence and duration of all trial periods, including follow-up,
if any.

6.4.6 A description of the "stopping rules" or "discontinuation
criteria" for individual subjects, parts of trial and entire trial.

6.4.7 Accountability procedures for the investigational product(s),
including the placebo(s) and comparator(s), if any.

6.5 Selection and Withdrawal of Subjects

When and how to withdraw subjects from the trial/ investigational
product treatment.

The type and timing of the data to be collected for withdrawn subjects.

Whether and how subjects are to be replaced.

The follow-up for subjects withdrawn from investigational product
treatment/trial treatment.

6.6 Treatment of Subjects

6.6.1 The treatment(s) to be administered, including the name(s) of
all the product(s), the dose(s), the dosing schedule(s), the route/mode(s)
of administration, and the treatment period(s), including the follow-up
period(s) for subjects for each investigational product treatment/trial
treatment group/arm of the trial.

6.6.2 Medication(s)/treatment(s) permitted (including rescue medication)
and not permitted before and/or during the trial.

6.6.3 Procedures for monitoring subject compliance.

6.7 Assessment of Efficacy

6.7.1 Specification of the efficacy parameters.

6.7.2 Methods and timing for assessing, recording, and analysing of
efficacy parameters.

6.8 Assessment of Safety

6.8.1 Specification of safety parameters.

6.8.2 The methods and timing for assessing, recording, and analysing
safety parameters.

6.8.3 Procedures for eliciting reports of and for recording and reporting
adverse event and intercurrent illnesses.

6.8.4 The type and duration of the follow-up of subjects after adverse
events.

6.9 Statistics

6.9.1 A description of the statistical methods to be employed, including
timing of any planned interim analysis(ses).

6.9.2 The number of subjects planned to be enrolled. In multicentre trials,
the numbers of enrolled subjects projected for each trial site should
be specified. Reason for choice of sample size, including reflections
on (or calculations of) the power of the trial and clinical justification.

6.9.3 The level of significance to be used.

6.9.4 Criteria for the termination of the trial.

6.9.5 Procedure for accounting for missing, unused, and spurious data.

6.9.6 Procedures for reporting any deviation(s) from the original statistical
plan (any deviation(s) from the original statistical plan should be described
and justified in protocol and/or in the final report, as appropriate).

6.9.7 The selection of subjects to be included in the analyses (e.g.,
all randomized subjects, all dosed subjects, all eligible subjects, evaluable
subjects).

6.10 Direct Access to Source Data/Documents

The sponsor should ensure that it is specified in the protocol or other
written agreement that the investigator(s)/institution(s) will permit
trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s),
providing direct access to source data/documents.

6.11 Quality Control and Quality Assurance Procedures

6.12 Ethics

Description of ethical considerations relating to the trial.

6.13 Data Handling and Record Keeping

6.14 Financing and Insurance

Financing and insurance if not addressed in a separate agreement.

6.15 Publication Policy

Publication policy, if not addressed in a separate agreement.

6.16 Supplements

(NOTE: Since the protocol and the clinical trial/study report are closely
related, further relevant information can be found in the ICH Guidance
for Structure and Content of Clinical Study Reports.)

7. Investigator's Brochure

7.1 Introduction

The Investigator's Brochure (IB) is a compilation of the clinical and
nonclinical data on the investigational product(s) that are relevant to
the study of the product(s) in human subjects. Its purpose is to provide
the investigators and others involved in the trial with the information
to facilitate their understanding of the rationale for, and their compliance
with, many key features of the protocol, such as the dose, dose frequency/interval,
methods of administration: and safety monitoring procedures. The IB also
provides insight to support the clinical management of the study subjects
during the course of the clinical trial. The information should be presented
in a concise, simple, objective, balanced, and non-promotional form that
enables a clinician, or potential investigator, to understand it and make
his/her own unbiased risk-benefit assessment of the appropriateness of
the proposed trial. For this reason, a medically qualified person should
generally participate in the editing of an IB, but the contents of the
IB should be approved by the disciplines that generated the described
data.

This guidance delineates the minimum information that should be included
in an IB and provides suggestions for its layout. It is expected that
the type and extent of information available will vary with the stage
of development of the investigational product. If the investigational
product is marketed and its pharmacology is widely understood by medical
practitioners, an extensive IB may not be necessary. Where permitted by
regulatory authorities, a basic product information brochure, package
leaflet, or labelling may be an appropriate alternative, provided that
it includes current, comprehensive, and detailed information on all aspects
of the investigational product that might be of importance to the investigator.
If a marketed product is being studied for a new use (i.e., a new indication),
an IB specific to that new use should be prepared. The IB should be reviewed
at least annually and revised as necessary in compliance with a sponsor's
written procedures. More frequent revision may be appropriate depending
on the stage of development and the generation of relevant new information.
However, in accordance with Good Clinical Practice, relevant new information
may be so important that it should be communicated to the investigators,
and possibly to the Institutional Review Boards (IRBs)/Independent Ethics
Committees (IECs) and/or regulatory authorities before it is included
in a revised IB.

Generally, the sponsor is responsible for ensuring that an up-to-date
IB is made available to the investigator(s) and the investigators are
responsible for providing the up-to-date IB to the responsible IRBs/IECs.
In the case of an investigator sponsored trial, the sponsor-investigator
should determine whether a brochure is available from the commercial manufacturer.
If the investigational product is provided by the sponsor-investigator,
then he or she should provide the necessary information to the trial personnel.
In cases where preparation of a formal IB is impractical, the sponsor-investigator
should provide, as a substitute, an expanded background information section
in the trial protocol that contains the minimum current information described
in this guidance.

7.2 General Considerations

The IB should include:

7.2.1 Title Page

This should provide the sponsor's name, the identity of each investigational
product (i.e., research number, chemical or approved generic name, and
trade name(s) where legally permissible and desired by the sponsor), and
the release date. It is also suggested that an edition number, and a reference
to the number and date of the edition it supersedes, be provided. An example
is given in Appendix 1.

7.2.2 Confidentiality Statement

The sponsor may wish to include a statement instructing the investigator/recipients
to treat the IB as a confidential document for the sole information and
use of the investigator's team and the IRB/IEC.

7.3 Contents of the Investigator's Brochure

The IB should contain the following sections, each with literature references
where appropriate:

7.3.1 Table of Contents

An example of the Table of Contents is given in Appendix 2

7.3.2 Summary

A brief summary (preferably not exceeding two pages) should be given,
highlighting the significant physical, chemical, pharmaceutical, pharmacological,
toxicological, pharmacokinetic, metabolic, and clinical information available
that is relevant to the stage of clinical development of the investigational
product.

7.3.3 Introduction

A brief introductory statement should be provided that contains the
chemical name (and generic and trade name(s) when approved) of the investigational
product(s), all active ingredients, the investigational product'(s') pharmacological
class and its expected position within this class (e.g., advantages),
the rationale for performing research with the investigational product(s),
and the anticipated prophylactic, therapeutic, or diagnostic indication(s).
Finally, the introductory statement should provide the general approach
to be followed in evaluating the investigational product.

A description should be provided of the investigational product substance(s)
(including the chemical and/or structural formula(e)), and a brief summary
should be given of the relevant physical, chemical, and pharmaceutical
properties.

To permit appropriate safety measures to be taken in the course of the
trial, a description of the formulation(s) to be used, including excipients,
should be provided and justified if clinically relevant. Instructions
for the storage and handling of the dosage form(s) should also be given.

Any structural similarities to other known compounds should be mentioned.

7.3.5 Nonclinical Studies

Introduction:

The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic,
and investigational product metabolism studies should be provided in summary
form. This summary should address the methodology used, the results, and
a discussion of the relevance of the findings to the investigated therapeutic
and the possible unfavourable and unintended effects in humans.

The information provided may include the following, as appropriate, if
known/available:

Species tested

Number and sex of animals in each group

Unit dose (e.g., milligram/kilogram (mg/kg))

Dose interval

Route of administration

Duration of dosing

Information on systemic distribution

Duration of post-exposure follow-up

Results, including the following aspects:

Nature and frequency of pharmacological or toxic effects

Severity or intensity of pharmacological or toxic effects

Time to onset of effects

Reversibility of effects

Duration of effects

Dose response

Tabular format/listings should be used whenever possible to enhance
the clarity of the presentation.

The following sections should discuss the most important findings from
the studies, including the dose response of observed effects, the relevance
to humans, and any aspects to be studied in humans. If applicable, the
effective and nontoxic dose findings in the same animal species should
be compared (i.e., the therapeutic index should be discussed). The relevance
of this information to the proposed human dosing should be addressed.
Whenever possible, comparisons should be made in terms of blood/tissue
levels rather than on a mg/kg basis.

Nonclinical Pharmacology

A summary of the pharmacological aspects of the investigational product
and, where appropriate, its significant metabolites studied in animals,
should be included. Such a summary should incorporate studies that assess
potential therapeutic activity (e.g., efficacy models, receptor binding,
and specificity) as well as those that assess safety (e.g., special
studies to assess pharmacological actions other than the intended therapeutic
effect(s)).

Pharmacokinetics and Product Metabolism in Animals

A summary of the pharmacokinetics and biological transformation and
disposition of the investigational product in all species studied should
be given. The discussion of the findings should address the absorption
and the local and systemic bioavailability of the investigational product
and its metabolites, and their relationship to the pharmacological and
toxicological findings in animal species.

Toxicology

A summary of the toxicological effects found in relevant studies conducted
in different animal species should be described under the following
headings where appropriate:

Single dose

Repeated dose

Carcinogenicity

Special studies (e.g., irritancy and sensitisation)

Reproductive toxicity

Genotoxicity (mutagenicity)

7.3.6 Effects in Humans

Introduction:

A thorough discussion of the known effects of the investigational product(s)
in humans should be provided, including information on pharmacokinetics,
metabolism, pharmacodynamics, dose response, safety, efficacy, and other
pharmacological activities. Where possible, a summary of each completed
clinical trial should be provided. Information should also be provided
regarding results of any use of the investigational product(s) other than
from clinical trials, such as from experience during marketing.

Pharmacokinetics and Product Metabolism in Humans

A summary of information on the pharmacokinetics of the investigational
product(s) should be presented, including the following, if available:

Other pharmacokinetic data (e.g., results of population studies
performed within clinical trial(s).

Safety and Efficacy

A summary of information should be provided about the investigational
product's/products' (including metabolites, where appropriate) safety,
pharmacodynamics, efficacy, and dose response that were obtained from
preceding trials in humans (healthy volunteers and/or patients). The
implications of this information should be discussed. In cases where
a number of clinical trials have been completed, the use of summaries
of safety and efficacy across multiple trials by indications in subgroups
may provide a clear presentation of the data. Tabular summaries of adverse
drug reactions for all the clinical trials (including those for all
the studied indications) would be useful. Important differences in adverse
drug reaction patterns/incidences across indications or subgroups should
be discussed.

The IB should provide a description of the possible risks and adverse
drug reactions to be anticipated on the basis of prior experiences with
the product under investigation and with related products. A description
should also be provided of the precautions or special monitoring to
be done as part of the investigational use of the product(s).

Marketing Experience

The IB should identify countries where the investigational product
has been marketed or approved. Any significant information arising from
the marketed use should be summarised (e.g., formulations, dosages,
routes of administration, and adverse product reactions). The IB should
also identify all the countries where the investigational product did
not receive approval/registration for marketing or was withdrawn from
marketing/registration.

7.3.7 Summary of Data and Guidance for the Investigator

This section should provide an overall discussion of the nonclinical
and clinical data, and should summarise the information from various sources
on different aspects of the investigational product(s), wherever possible.
In this way, the investigator can be provided with the most informative
interpretation of the available data and with an assessment of the implications
of the information for future clinical trials.

Where appropriate, the published reports on related products should
be discussed. This could help the investigator to anticipate adverse drug
reactions or other problems in clinical trials.

The overall aim of this section is to provide the investigator
with a clear understanding of the possible risks and adverse reactions,
and of the specific tests, observations, and precautions that may be needed
for a clinical trial. This understanding should be based on the available
physical, chemical, pharmaceutical, pharmacological, toxicological, and
clinical information on the investigational product(s). Guidance should
also be provided to the clinical investigator on the recognition and treatment
of possible overdose and adverse drug reactions that is based on previous
human experience and on the pharmacology of the investigational product.

8. Essential Documents For The Conduct Of A Clinical
Trial

8.1 Introduction

Essential Documents are those documents which individually and collectively
permit evaluation of the conduct of a trial and the quality of the data
produced. These documents serve to demonstrate the compliance of the investigator,
sponsor and monitor with the standards of Good Clinical Practice and with
all applicable regulatory requirements.

Essential Documents also serve a number of other important purposes.
Filing essential documents at the investigator/institution and sponsor
sites in a timely manner can greatly assist in the successful management
of a trial by the investigator, sponsor and monitor. These documents are
also the ones which are usually audited by the sponsor's independent audit
function and inspected by the regulatory authority(ies) as part of the
process to confirm the validity of the trial conduct and the integrity
of data collected.

The minimum list of essential documents which has been developed follows.
The various documents are grouped in three sections according to the stage
of the trial during which they will normally be generated: 1) before the
clinical phase of the trial commences, 2) during the clinical conduct
of the trial, and 3) after completion or termination of the trial. A description
is given of the purpose of each document, and whether it should be filed
in either the investigator/institution or sponsor files, or both. It is
acceptable to combine some of the documents, provided the individual elements
are readily identifiable.

Trial master files should be established at the beginning of the trial,
both at the investigator/institution's site and at the sponsor's office.
A final close-out of a trial can only be done when the monitor has reviewed
both investigator/institution and sponsor files and confirmed that all
necessary documents are in the appropriate files.

Any or all of the documents addressed in this guidance may be subject
to, and should be available for, audit by the sponsor's auditor and inspection
by the regulatory authority(ies).

8.2 Before the Clinical Phase of the Trial Commences

During this planning stage the following documents should be generated
and should be on file before the trial formally starts

Before the Clinical Phase of the Trial Commences

Title of Document

Purpose

Located in Files of

Investigator/
Institution

Sponsor

8.2.1 INVESTIGATOR'S BROCHURE

To document that relevant and current scientific information about the investigational product has been provided to the investigator

X

X

8.2.2 SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)

To document investigator and sponsor agreement to the protocol/
amendment(s) and CRF

X

X

8.2.3 INFORMATION GIVEN TO TRIAL SUBJECT

- INFORMED CONSENT FORM (including all applicable translations)

To document the informed consent

X

X

- ANY OTHER WRITTEN INFORMATION

To document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent

X

X

-ADVERTISEMENT FOR SUBJECT RECRUITMENT(if used)

To document that recruitment measures are appropriate and not coercive

X

8.2.4 FINANCIAL ASPECTS OF THE TRIAL

To document the financial agreement between the investigator /institution and the sponsor for the trial

X

X

8.2.5 INSURANCE STATEMENT
(where required)

To document that compensation to subject(s) for trial-related injury will be available

Notification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11

X

X

8.3.17 NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION

Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2

X
(where required)

X

8.3.18 NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY
INFORMATION

Notification by sponsor to investigators of safety information in accordance with 5.16.2

X

X

8.3.19 INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)

Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3

X

X
(where required)

8.3.20 SUBJECT SCREENING LOG

To document identification of subjects who entered pre-trial screening

X

X
(where required)

8.3.21 SUBJECT IDENTIFICATION CODE LIST

To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/ institution to reveal identity of any subject

X

8.3.22 SUBJECT ENROLLMENT LOG

To document chronological enrollment of subjects by trial number

X

8.3.23 INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITE

To document that investigational product(s) have been used according to the protocol

X

X

8.3.24 SIGNATURE SHEET

To document signatures and initials of all persons authorised to make entries and/or corrections on CRFs

X

X

8.3.25 RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)

To document location and identification of retained samples if assays need to be repeated

X

X

8.4 After Completion or Termination of the Trial

After completion or termination of the trial, all of the documents identified in sections 8.2 and 8.3 should be in the file together with the following

After Completion or Termination of the Trial

Title of Document

Purpose

Located in Files of

Investigator/
Institution

Sponsor

8.4.1 INVESTIGATIONAL PRODUCT(S) ACCOUNTABILITY AT SITE

To document that the investigational product(s) have been used according to the protocol. To document the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor

X

X

8.4.2 DOCUMENTATION OF INVESTIGATIONAL PRODUCT DESTRUCTION

To document destruction of unused investigational products by sponsor or at site

X
(if destroyed at site)

X

8.4.3 COMPLETED SUBJECT IDENTIFICATION CODE LIST

To permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time

X

8.4.4 AUDIT CERTIFICATE (if available)

To document that audit was performed

X

8.4.5 FINAL TRIAL CLOSE-OUT MONITORING REPORT

To document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files

X

8.4.6 TREATMENT ALLOCATION AND DECODING DOCUMENTATION

Returned to sponsor to document any decoding that may have occurred

X

8.4.7 FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)

To document completion of the trial

X

8.4.8 CLINICAL STUDY REPORT

To document results and interpretation of trial

X
(if applicable)

X

Footnotes

Footnote 1

International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use